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A Correction to this paper has been published: https://doi.org/10.1038/s41591-020-01186-5

Improved understanding and management of COVID-19, a potentially life-threatening disease, could greatly reduce the threat posed by its etiologic agent, SARS-CoV-2. Toward this end, we have identified a core peripheral blood immune signature across 63 hospital-treated patients with COVID-19 who were otherwise highly heterogeneous. The signature includes discrete changes in B and myelomonocytic cell composition, profoundly altered T cell phenotypes, selective cytokine/chemokine upregulation and SARS-CoV-2-specific antibodies. Some signature traits identify links with other settings of immunoprotection and immunopathology; others, including basophil and plasmacytoid dendritic cell depletion, correlate strongly with disease severity; while a third set of traits, including a triad of IP-10, interleukin-10 and interleukin-6, anticipate subsequent clinical progression. Hence, contingent upon independent validation in other COVID-19 cohorts, individual traits within this signature may collectively and individually guide treatment options; offer insights into COVID-19 pathogenesis; and aid early, risk-based patient stratification that is particularly beneficial in phasic diseases such as COVID-19. A common immune signature in the blood of patients with COVID-19, who are otherwise clinically heterogeneous, sheds light into the pathogenesis and clinical progression of the disease.

Sibutramine is a centrally acting monoamine reuptake inhibitor prescribed as an appetite suppressant in the management of obesity. Its effects are mostly attributable to serotonin and norepinephrine transporter (SERT and NET, respectively) inhibition by its potent metabolites mono-desmethylsibutramine (M1) and di-desmethylsibutramine (M2). However, there is a paucity of in vivo data in humans about mechanisms underlying both clinical efficacy and the dose-independent non-response observed in a minority of patients. Twelve healthy male patients (mean age 41 years) completed a double-blind, placebo-controlled, within-subject crossover investigation of brain SERT occupancy by sibutramine 15 mg daily at steady state. Correlations were measured between occupancy and (i) plasma concentrations of sibutramine, M1 and M2; (ii) appetite suppression. (11)C-DASB PET scans were performed on the HRRT camera. Binding potentials (BP(ND)) were calculated by the Logan reference tissue (cerebellum) method. SERT occupancy was modest (mean 30+/-10%), was similar across brain regions, but varied widely across subjects (15-46%). Occupancy was correlated positively (p=0.09) with M2 concentration, but not with sibutramine or M1. No significant appetite suppression was seen at <25% occupancy and greatest suppression was associated with highest occupancy (25-46%). However, several subjects with occupancy (36-39%) in the higher range had no appetite suppression. SERT occupancy by clinical doses of sibutramine is of modest magnitude and may be mediated predominantly by M2 in humans. 5-HT reuptake inhibition may be necessary but is not sufficient for sibutramine's efficacy in humans, supporting preclinical data suggesting that the hypophagic effect requires the co-inhibition of both SERT and NET.

Improved understanding and management of COVID-19, a potentially life-threatening disease, could greatly reduce the threat posed by its etiologic agent, SARS-CoV-2. Toward this end, we have identified a core peripheral blood immune signature across 63 hospital-treated patients with COVID-19 who were otherwise highly heterogeneous. The signature includes discrete changes in B and myelomonocytic cell composition, profoundly altered T cell phenotypes, selective cytokine/chemokine upregulation and SARS-CoV-2-specific antibodies. Some signature traits identify links with other settings of immunoprotection and immunopathology; others, including basophil and plasmacytoid dendritic cell depletion, correlate strongly with disease severity; while a third set of traits, including a triad of IP-10, interleukin-10 and interleukin-6, anticipate subsequent clinical progression. Hence, contingent upon independent validation in other COVID-19 cohorts, individual traits within this signature may collectively and individually guide treatment options; offer insights into COVID-19 pathogenesis; and aid early, risk-based patient stratification that is particularly beneficial in phasic diseases such as COVID-19. A common immune signature in the blood of patients with COVID-19, who are otherwise clinically heterogeneous, sheds light into the pathogenesis and clinical progression of the disease.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Sibutramine is a centrally acting monoamine reuptake inhibitor prescribed as an appetite suppressant in the management of obesity. Its effects are mostly attributable to serotonin and norepinephrine transporter (SERT and NET, respectively) inhibition by its potent metabolites mono-desmethylsibutramine (M1) and di-desmethylsibutramine (M2). However, there is a paucity of in vivo data in humans about mechanisms underlying both clinical efficacy and the dose-independent non-response observed in a minority of patients. Twelve healthy male patients (mean age 41 years) completed a double-blind, placebo-controlled, within-subject crossover investigation of brain SERT occupancy by sibutramine 15mg daily at steady state. Correlations were measured between occupancy and (i) plasma concentrations of sibutramine, M1 and M2; (ii) appetite suppression. super(11)C-DASB PET scans were performed on the HRRT camera. Binding potentials (BP sub(ND)) were calculated by the Logan reference tissue (cerebellum) method. SERT occupancy was modest (mean 30 plus or minus 10%), was similar across brain regions, but varied widely across subjects (15-46%). Occupancy was correlated positively (p=0.09) with M2 concentration, but not with sibutramine or M1. No significant appetite suppression was seen at <25% occupancy and greatest suppression was associated with highest occupancy (25-46%). However, several subjects with occupancy (36-39%) in the higher range had no appetite suppression. SERT occupancy by clinical doses of sibutramine is of modest magnitude and may be mediated predominantly by M2 in humans. 5-HT reuptake inhibition may be necessary but is not sufficient for sibutramine's efficacy in humans, supporting preclinical data suggesting that the hypophagic effect requires the co-inhibition of both SERT and NET.

Sibutramine is a centrally acting monoamine reuptake inhibitor prescribed as an appetite suppressant in the management of obesity. Its effects are mostly attributable to serotonin and norepinephrine transporter (SERT and NET, respectively) inhibition by its potent metabolites mono-desmethylsibutramine (M1) and di-desmethylsibutramine (M2). However, there is a paucity of in vivo data in humans about mechanisms underlying both clinical efficacy and the dose-independent non-response observed in a minority of patients. Twelve healthy male patients (mean age 41 years) completed a double-blind, placebo-controlled, within-subject crossover investigation of brain SERT occupancy by sibutramine 15 mg daily at steady state. Correlations were measured between occupancy and (i) plasma concentrations of sibutramine, M1 and M2; (ii) appetite suppression. 11 C-DASB PET scans were performed on the HRRT camera. Binding potentials (BP ND ) were calculated by the Logan reference tissue (cerebellum) method. SERT occupancy was modest (mean 30±10%), was similar across brain regions, but varied widely across subjects (15–46%). Occupancy was correlated positively ( p =0.09) with M2 concentration, but not with sibutramine or M1. No significant appetite suppression was seen at <25% occupancy and greatest suppression was associated with highest occupancy (25–46%). However, several subjects with occupancy (36–39%) in the higher range had no appetite suppression. SERT occupancy by clinical doses of sibutramine is of modest magnitude and may be mediated predominantly by M2 in humans. 5-HT reuptake inhibition may be necessary but is not sufficient for sibutramine's efficacy in humans, supporting preclinical data suggesting that the hypophagic effect requires the co-inhibition of both SERT and NET.

Artificial Intelligence methods are powerful tools for biological image analysis and processing. High-quality annotated images are key to training and developing new methods, but access to such data is often hindered by the lack of standards for sharing datasets. We brought together community experts in a workshop to develop guidelines to improve the reuse of bioimages and annotations for AI applications. These include standards on data formats, metadata, data presentation and sharing, and incentives to generate new datasets. We are positive that the MIFA (Metadata, Incentives, Formats, and Accessibility) recommendations will accelerate the development of AI tools for bioimage analysis by facilitating access to high quality training data.

Artificial Intelligence methods are powerful tools for biological image analysis and processing. High-quality annotated images are key to training and developing new methods, but access to such data is often hindered by the lack of standards for sharing datasets. We brought together community experts in a workshop to develop guidelines to improve the reuse of bioimages and annotations for AI applications. These include standards on data formats, metadata, data presentation and sharing, and incentives to generate new datasets. We are positive that the MIFA (Metadata, Incentives, Formats, and Accessibility) recommendations will accelerate the development of AI tools for bioimage analysis by facilitating access to high quality training data.